The present invention is generally concerned with a novel polymorphic form of fluoxetine hydrochloride, (xc2x1)-N-methyl-3-phenyl-2-[xcex1,xcex1,xcex1-trifluoro-p-tolyl) oxy]propylamine hydrochloride, which is marketed by Dista Products and Eli Lilly and Company (the xe2x80x9cInnovatorxe2x80x9d), Indianapolis, Ind., under the trade name Prozac(copyright). The present invention is further concerned with the preparation and use of the polymorphic form of fluoxetine hydrochloride now designated Form A (xe2x80x9cForm Axe2x80x9d).
Polymorphic forms of the same drug substance (also known as the active pharmaceutical ingredient or xe2x80x9cAPIxe2x80x9d), as administered by itself or formulated as a drug product (also known as the final or finished dosage form) are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, fractability, and compressibility of drug substances and the safety and efficacy of drug products, (see, e.g. Knapman, K. Modern Drug Discoveries, March, 2000: 53). So critical are the potential effects of different polymorphic forms in a single drug substance on the safety and efficacy of the respective drug product(s) that the United States Food and Drug Administration (the xe2x80x9cFDAxe2x80x9d) requires each drug substance manufacturer, in the least, to control its synthetic processes such that the percentages of the various respective polymorphic forms, when present, must be consistent among batches and within the drug substance/product""s specification as approved by the FDA.
Left uncontrolled in synthetic processes, the percentage of a given polymorph outside of an FDA approved specification would render the adulterated batches unfit for commercial sale. Accordingly, the FDA requires fall characterization of each drug substance used in each drug product marketed in the United States, including the identification and control of polymorphic forms. The FDA further requires robust synthetic process specifications and controls which consistently produce the respective drug substance and drug product. Unfortunately, the detection of various polymorphic forms of a single drug substance is not always readily discernable by pharmaceutical chemists. Such a drug substance would not be manufactured with appropriate controls, potentially leaving the attendant safety and efficacy risks unaddressed.
It has been discovered that fluoxetine hydrochloride drug substance, generally used to prepare Prozac(copyright) and potential generic drugs thereto (fluoxetine hydrochloride API), has not been fully or completely characterized. It has been unexpectedly discovered that such fluoxetine hydrochloride API drug substance comprises at least three crystalline forms, which occur at varying and uncontrolled ratios from batch to batch. These three identified polymorphs have been designated Form A, Form B, and Form C, correlated to the relative proportion of each polymorph in fluoxetine hydrochloride, from greatest to least.
It has further been discovered that Form A can be prepared in pure or essentially pure polymorphic form in robust, controllable, synthetic processes.